Red wine, chocolate and vascular health: developing the evidence base
- Professor R Corder, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK; r.corder{at}qmul.ac.uk
More than 30 years’ research have emphasised that lifestyle, exercise, diet and weight reduction are by far the most effective strategies to cut the risk of coronary heart disease (CHD). Alcohol consumption, as a protective habit, has attracted considerable attention. Meta-analyses have demonstrated consistently both protection from CHD and reductions in total mortality.1 2 In fact, moderate alcohol drinkers with a healthy diet who are not overweight have a reduced incidence of myocardial infarction compared with those with similar habits who abstain from alcohol.3 Regular moderate drinking of alcohol after acute myocardial infarction affords at least a similar level of protection from further events as drug treatment, and has also proved beneficial after coronary stenting.4–6
Wine has often been the preferred drink for those showing the greatest degree of protection, yet controversy has raged as to whether the benefits are from alcohol alone, or from other constituents of wine. Regular alcohol drinking augments high-density lipoprotein cholesterol and can increase insulin sensitivity or reduce diabetes, which both provide a degree of protection from CHD.7–9 Although the biggest focus has been on CHD, other atherothrombotic conditions merit consideration. For instance, red wine consumption reduced the incidence of ischaemic stroke when white wine and other alcoholic drinks did not provide any protection,10 which supports the opinion that red wine has greater anti-atherosclerotic or antithrombotic actions than alcohol alone because it contains a variety of polyphenols with their own profile of protective properties. The emerging theme from recent investigations of red wine polyphenols is the close similarity to the actions of dark chocolate or cocoa.
The beneficial effects of polyphenols, including those from red wine and cocoa, have often been attributed to their antioxidant actions. But the general conclusion from studies over the past few years is that the absorption of polyphenols is insufficient for exerting any antioxidant effect. Consequently, research is moving to the identification of specific functional effects at the nmol/l to low μmol/l concentrations achieved after oral consumption. Two key themes of interest have developed to explain the cardiovascular benefits of red wine and cocoa: interactions with vascular endothelial function, and modulation of platelet aggregation. Further research in this area is likely to disclose new dietary or pharmaceutical approaches to reduce thrombosis risk and treat endothelial dysfunction.
SIMILARITY BETWEEN ACTIONS OF DARK CHOCOLATE AND RED WINE POLYPHENOLS
Observational studies have shown the absence of age-related increases in blood pressure in Kuna Indians drinking high quantities of polyphenol-rich cocoa.11 In addition, men in the Zutphen Elderly Study with the highest tertile of daily cocoa consumption had lower blood pressure and reduced cardiovascular mortality.12 A number of small clinical trials have also described modest decreases in blood pressure with dark chocolate.13 Consistent with these findings, acute consumption of dark chocolate or cocoa increases flow-mediated dilatation (FMD) in the forearm.14 15 Given that reduced FMD is predictive of future CHD, and is also thought to be a key factor in age-related increases in blood pressure, it is interesting to note that the greatest improvement in FMD with cocoa was in those aged over 50.15 FMD responses are also increased by red wine polyphenols consumed as alcohol-free wine.16 Treatment with red wine polyphenols also augments coronary flow velocity reserve in patients with CHD and control subjects.17 Hence, a common mechanism for improving endothelial function seems likely for red wine and cocoa polyphenols.
Consumption of purple grape juice, dark chocolate, or cocoa reduces platelet aggregation,14 18 19 which indicates a specific polyphenol-mediated action on platelets.
RED WINE AND COCOA POLYPHENOLS
Flavonoids are a group of naturally occurring polyphenolic phytochemicals that are common in fruit and also found in tea and some vegetables.20 People with high flavonoid intake have a lower incidence of CHD.21 Red wine and cocoa are rich sources of a group of flavonoids called flavan-3-ols. Flavanols are present either as monomers, (−)-epicatechin and (+)-catechin, or oligomers of epicatechin and catechin called procyanidins.20 In red wine, procyanidins form esters with gallic acid, and also react with anthocyanins (the coloured flavonoids found in grape skin) to produce proanthocyanidins. Procyanidins in red wine are derived mainly from the grape seeds, but owing to their poor solubility, seeds need to be present in the fermenting must for at least 10–14 days for extraction of maximum amounts. Shorter periods used for mass-produced red wines are leading to wines virtually devoid of procyanidins.22 White wines do not contain procyanidins because the juice is fermented without seeds or skin.
Manufacturing processes also affect levels of flavanols in chocolate products. Fermentation of cocoa beans, although an essential step in chocolate manufacture, leads to a progressive loss of both epicatechin and procyanidins, with many popular brands being largely depleted of flavanols. It is frequently stated that dark chocolate is a richer-source of flavonoids (often just referred to as antioxidants) than red wine.14 This is misleading because if it is based on a serving of similar calorific value this difference is no longer apparent (fig 1). There are also large variations for both red wine and dark chocolate, so a generalisation that one is a better choice is unreliable. A future requirement for product labels to include information on flavanol content is essential for consumers.
Some attribute the vasoactive properties of red wine to resveratrol. This is a minor stilbene polyphenol found in some wines (generally <2 mg/l; compared with total polyphenols of up to 5 g/l and procyanidins up to 2 g/l). To achieve beneficial effects from resveratrol requires at least 1000-fold greater amounts than can be achieved through drinking red wine.23
BIOLOGICAL ACTIVITY OF FLAVANOLS
Epicatechin and catechin have virtually no biological activity on vascular preparations, cultured endothelial cells, or isolated platelets.24–26 In these in vitro systems the biological activity of red wine and dark chocolate can be accounted for by procyanidins/proanthocyanidins as they induce endothelium-dependent vasodilatation, suppress endothelin-1 synthesis, and inhibit platelet aggregation at low μmol/l or nmol/l concentrations.18 22 25 27
Demonstrating this in vivo has proved more difficult. This is mainly because measurement of procyanidins in plasma has proved technically difficult, leading some to conclude that they are not absorbed.28 One study of high flavanol cocoa in volunteers concluded that increased FMD responses were due to (−)-epicatechin,29 but close examination of the data shows the magnitude of the response to epicatechin was approximately one-third of that obtained with cocoa. Also, this study failed to confirm the conclusions by testing cocoa procyanidins, or cocoa that had been depleted of epicatechin.
Absorption of procyanidins at functionally relevant concentrations has been described in rodent studies.30 Considerably more work on human bioavailability is needed, including evaluations of factors affecting absorption.
MECHANISM OF ACTION OF FLAVANOLS ON THE ENDOTHELIUM
In isolated vessels endothelium-dependent vasodilator responses to procyanidins are rapid in onset. Evidence of a structure–activity relationship is consistent with these responses being mediated by a procyanidin receptor,22 25 27 which could represent an important drug discovery target for new agents to treat endothelial dysfunction. This response involves signalling through superoxide or hydrogen peroxide,31 so might even be considered pro-oxidant. Flow-mediated dilatation also involves signalling through hydrogen peroxide.32 Hence, these findings are consistent with the hypothesis that procyanidins trigger an endothelial response similar to that of laminar shear stress.33
EVIDENCE TO SUPPORT FUTURE HEALTH CLAIMS
Regulations governing health claims for food and nutritional supplements are becoming more rigorous. This is important, as it will lead to the level of evidence required for introducing sound consumer guidelines for new products.34 This should prevent flawed advice such as recommendations to eat margarine because it is low in saturated fat, which led many consumers to switch, only for the presence of hydrogenated trans fats in these products to be later linked to an increased risk of CHD.35
So should health claims be allowed for any food without long-term outcome studies? Currently, this is not likely to be a requirement, but a greater emphasis will be placed on demonstrating a biologically meaningful benefit. So minimal changes in low-density lipoprotein cholesterol, such as those achieved with products containing phytosterols and stanols, may not be sufficient to justify an allowable health claim given the lack of information on the benefits of cholesterol lowering with agents other than statins. Particularly when estimates of the number needed to treat indicate that up to 1000 people need to consume phytosterol-enriched products daily to prevent even one CHD death.36
Clinical trials of red wine leading to health claims are unlikely on ethical and safety grounds. Nevertheless, some carefully controlled studies in volunteers could provide useful insights into the relative importance of alcohol versus polyphenol constituents on vascular function and antithrombotic effects.
What are the key areas to be examined for cocoa or grape-derived foods or supplements that are seeking to make health claims? First, the relative importance of the different flavanol components (epicatechin versus procyanidins) needs to be fully established, as well as the factors affecting their bioavailability and metabolism. Second, for assessing responses to these products, validated biological markers are needed that are predictive of reduced cardiovascular mortality or morbidity. This is a difficult area even for prescription medicines as the limitations of measuring blood pressure or low-density lipoprotein cholesterol are becoming increasingly apparent when considered in terms of predicting a person’s future risk once appropriate treatment has been introduced. To rapidly advance our understanding of the benefits of cocoa and red wine, better means of assessing endothelial and platelet function are required in order to identify those people at highest risk of CHD, monitor their response during interventions, and define the optimal daily consumption for improving vascular health. Based on the evidence to date, there should be a degree of optimism that well-characterised flavanol-rich products will appear with a body of evidence to support meaningful benefits and justify health claims.
Footnotes
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Competing interests: Roger Corder is the author of The Wine Diet. He has received funding from wine, beverage and chocolate companies to support research and to attend conferences and meetings.
